Eukaryotes have evolved a complex system to regulate access to genomic information by packaging DNA into chromatin. Chromatin can adopt various levels of organization that regulate essential cellular activities such as transcription, DNA replication, recombination, and repair. The fundamental repeating unit of chromatin is the nucleosome in which base pairs of genomic DNA is wrapped around a disc-shaped octamer of histone proteins: H2A, H2B, H3 and H4. Nucleosome positioning on DNA is fundamentally involved in controlling gene access and is regulated in part by a diverse array of enzymes that introduce covalent post-translation modifications on histone proteins. An extensive array of histone modifications have been characterized, including lysine methylation. The large number of potential histone modification patterns provide cells with an enormous combinatorial potential for the precise regulation of gene function.
The combinatory complexity of histone modifications is further increased by histone lysine residues that can be mono-, di-, or trimethylated, each of which are correlated with distinct functional outcomes. One such lysine residue that is involved in gene regulation is the fourth residue on the H3 histone protein (H3K4). Several enzymes that regulate H3K4 methylation have been identified, all possessing the evolutionarily conserved SET domain, which is required for lysine methylation. Members of the SET1 family of proteins assemble into multisubunit complexes that regulate mono-, di- and trimethylation. The most studied human SET1 family member is the mixed lineage leukemia protein-1 (MLL1) which is required for the regulation of hox genes in hematopoiesis and development. Others member of the human SET1 family include MLL2, MLL3, MLL4, SET1a and SET1b.
Recently, it has been shown that the minimal complex required for di- and trimethylation of H3K4 includes MLL1, WDR5, RbBP5 and Ash2L, which together form the MLL1 core complex. The protein WDR5 has been shown to be critical for these interactions, as it bridges the catalytic SET domain of SET1 family proteins and the regulatory components of RbBP5 and Ash2L.
Overproduction of the MLL1 core complex leads to excessive di- and trimethylation of H3K4 which disrupts gene regulation. This, in turn, alters hematopoiesis and normal development and has been linked to certain types of leukemia, solid tumors, and psychotropic disorders, such as schizophrenia and bipolar disorders.
Therefore, a method for inhibiting the formation of SET1 family core complexes is desired. It is also desired to inhibit the H3K4 dimethylation (H3K4me2) activity of SET1 family core complexes by inhibiting the formation of such complex.